Nilotinib: a new tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia.
Chronic myelogenous leukemia (CML) is a myeloproliferative disorder arising from a single genetic mutation that leads to an increase in immature myeloid cells in the bone marrow and the accumulation of these cells in the blood. Typically, CML represents 15-20% of all adult leukemias, with 4830 new cases expected in 2008. The cytogenetic hallmark of CML is the Philadelphia chromosome, which is the result of the reciprocal translocation and conjugation of the breakpoint cluster region (BCR) gene, BCR, on chromosome 22 and the Abelson (ABL) kinase gene, ABL, on chromosome 9. Current treatment is aimed at inhibiting BCR and ABL kinase with novel agents, the first being imatinib in 2003, and more recently dasatinib in 2006. Nilotinib is a new small-molecule inhibitor of tyrosine kinase rationally developed from the crystalline structure of the imatinib-ABL complex. It represents an aminopyrimidine derivative of imatinib with approximately 30 times more potency in vitro against imatinib-sensitive BCR-ABL-expressing cell lines and activity against 32 of 33 point mutations conferring resistance to imatinib. Data from phase I and II studies show that nilotinib has activity against all phases of CML in patients who are intolerant or have failed therapy with imatinib or dasatinib. Nilotinib represents a new therapeutic option for patients with CML who are intolerant or have failed therapy with imatinib. Ongoing clinical trials are assessing nilotinib's role in the treatment of patients with newly diagnosed CML and its long-term efficacy and safety.
Jarkowski
Anthony
A
Department of Pharmacy, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. Anthony.Jarkowski@roswellpark.org
Sweeney
Richard P
RP
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D017322:Clinical Trials, Phase II as Topic; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C498826:nilotinib